Chronic hepatitis C virus (HCV) infection is characterized by stable life long viremia and a substantially increased risk of serious progressive liver disease. HCV persists in part because T cell immunity fails. Studies in adults have shown that cytotoxic CD8+ T cells are functionally exhausted or target viral epitopes that have mutated to escape recognition. Loss of CD4+ T helper cell activity is a hallmark of chronic hepatitis C but mechanisms that silence this critical immune response have not been identified. Chronic HCV infection appears to be modified by pregnancy. Viremia often increases during pregnancy and then decreases, often by several logs, after childbirth. Our central hypothesis is that cellular immunity to HCV is fully restored, at least transiently, in the post-partum period. Two Specific Aims are proposed. Specific Aim 1 is to compare cellular immunity to HCV in women with and without a substantial drop in viremia in the postpartum period. Some women will be followed through two pregnancies so that virus replication and immunity can also be compared during and immediately after pregnancy, but also during a prolonged inter-pregnancy time period that is typical of chronic infection. Specifically we will test the hypothesis that women with a substantial drop in viremia after delivery have an increased frequency of HCV-specific T cells that target more viral proteins. In addition it is predicted that reversal of exhaustion is associated with acquisition of multiple effector functions, susceptibility to signals from survival cytokines, and decreased predisposition to apoptosis. Specific Aim 2 is to determine how changes in T cell immunity during and immediately after pregnancy influence evolution of HCV genomes. We predict that CD8+ T cell immunity is relaxed during pregnancy, so that escape mutations in some class I epitopes revert to a sequence that is more fit for HCV replication. If T cells do resurge after delivery as predicted in Specific Aim 1, we also expect to observe emergence (or reemergence) of escape mutations in class I epitopes. Spontaneous recovery of T cell immunity that restricts HCV replication would represent a significant departure from the typical pattern of chronic infection described in men and non-pregnant women. We believe that understanding the mechanism(s) of spontaneous HCV control after childbirth is relevant to human health. For instance it would provide insight into strategies to cure infection during a unique window of low virus replication in the mothers. The studies should also provide information on the relationship between replicative fitness and patterns of escape mutation in viruses that emerge late in pregnancy and are potentially transmissible to HLA semi-matched infants. More generally, the studies should provide a substantially new direction for unraveling the molecular basis of T cell dysfunction and approaches to immunomodulation in chronic hepatitis C.